© 1997 American Heart Association, Inc.
Articles |
Monocyte Chemotactic Protein-1 Increases Collateral and Peripheral Conductance After Femoral Artery Occlusion
From the Department of Experimental Cardiology, Max-Planck-Institute for Physiological and Clinical Research, Bad Nauheim, Germany.
Correspondence to Dr Wulf Ito, MD, Max-Planck-Institute for Physiological and Clinical Research, Department of Experimental Cardiology, Benekestrasse 2, D-61231 Bad Nauheim, Germany. E-mail wito{at}alpha.kerckhoff.mpg.de
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Abstract |
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Abstract Monocytes are activated during collateral artery growth in vivo, and monocyte chemotactic protein-1 (MCP-1) has been shown to be upregulated by shear stress in vitro. In order to investigate whether MCP-1 enhances collateral growth after femoral artery occlusion, 12 rabbits were randomly assigned to receive either MCP-1, PBS, or no local infusion via osmotic minipump. Seven days after occlusion, isolated hindlimbs were perfused with autologous blood at different pressures, measuring flows at maximal vasodilation via flow probe and radioactive microspheres, as well as peripheral pressures. This allowed the calculation of collateral (thigh) and peripheral (lower limb) conductances from pressure-flow tracings (slope of the curve). Collateral growth on postmortem angiograms was restricted to the thigh and was markedly enhanced with MCP-1 treatment. Both collateral and peripheral conductances were significantly elevated in animals with MCP-1 treatment compared with the control group, reaching values of nonoccluded hindlimbs after only 1 week of occlusion (collateral conductance, 70.6±19.23 versus 25.1±2.59 mL/min per 100 mm Hg; P<.01; peripheral conductance, 119.3±22.37 versus 45.4±6.80 mL/min per 100 mm Hg; P<.05). These results suggest that activation of monocytes plays an important role in collateral growth as well as in capillary sprouting.
Key Words: collateral artery growth • angiogenesis • monocyte • rabbit hindlimb
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Introduction |
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Vascular growth in adult organisms proceeds via two distinct mechanisms, sprouting of capillaries (angiogenesis) and in situ enlargement of preexisting arteriolar connections into true collateral arteries.1 Recent studies have disclosed mechanisms leading to angiogenesis with VEGF as a major component.2 3 4 5 6 This specific endothelial mitogen is upregulated by hypoxia and is able to promote vessel growth when infused into rabbit hindlimbs after femoral artery excision.7 8 However, these studies did not distinguish between capillary sprouting, a mechanism called angiogenesis, and true collateral artery growth. Whereas VEGF is only mitogenic for endothelial cells, collateral artery growth requires the proliferation of endothelial and smooth muscle cells and pronounced remodeling processes occur.1 9 10 11 12 Furthermore, capillary sprouting is mainly observed in ischemic territories (eg, in the pig heart or in rapidly growing tumors).1 3 13 14 True collateral artery growth, however, is temporally and spacially dissociated from ischemia in most models studied.1 15 Mechanisms in addition to those described for angiogenesis in ischemic territories are therefore needed to explain collateral artery growth. From previous studies, we know that these collateral arteries grow from preexisting arteriolar connections.1 Because the main arterial supply is impeded, pressure gradients develop along these arterioles, leading to the generation of shear force and cyclic strain. These mechanical forces have recently been shown to increase MCP-1 secretion in cultured human endothelial cells, leading to increased monocyte adhesion.16 17 18 These findings complement our observation that monocytes adhere and migrate into the vessel wall of collateral arteries after induction of coronary artery stenosis in the dog heart at a time when the proliferation index is maximally increased.19 Moreover, monocyte accumulation is also observed in the pig microembolization model of angiogenesis.20 When studying gene expression in this model, we found that the mRNA for MCP-1 was strongly upregulated shortly after microembolization.21
Therefore, on the basis of these findings, we investigated whether MCP-1 is able to enhance collateral artery growth as well as angiogenesis. In order to circumvent systemic side effects and ensure maximal dosage at the site of interest, we designed a method of local delivery into the collateral circulation. Collateral artery growth and angiogenesis were evaluated using a model we recently developed that allows the separation of both types of vessel growth after femoral artery occlusion in the rabbit hindlimb.
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Materials and Methods |
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Animal Model
The present study was performed with permission of the State of Hesse, Regierungspräsidium Darmstadt, according to section 8 of the German Law for the Protection of Animals. It conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). Twelve rabbits were subjected to 7 days of bilateral femoral artery occlusion. They were randomly assigned to either receive MCP-1 (PeproTech Inc) locally via osmotic minipump (2ML-2, Alza Corp; 3 µg in 2 mL PBS at a rate of 10 µL/h), PBS via osmotic minipump, or no treatment. Nine additional animals were subjected to no occlusion, acute occlusion, or 21 days of femoral artery occlusion for comparison. Two animals were supplied with an osmotic minipump (2ML-2, Alza Corp) delivering BrdU (Sigma Chemical Co) via the same route as MCP-1 to verify the function of our local delivery system and to study the proliferation of collateral arteries and capillaries.
For the initial surgery, the animals were anesthetized with an intramuscular injection of ketamine hydrochloride (40 to 80 mg/kg body wt) and xylazine (8 to 9 mg/kg body wt). Supplementary doses of anesthetic (10% to 20% of the initial dose) were given intravenously as needed. Surgery was performed under sterile conditions. Femoral arteries were exposed and cannulated with a sterile polyethylene catheter (inner diameter, 1 mm; outer diameter, 1.5 mm) pointing upstream, with the tip of the catheter positioned distal to the branching of the arteria circumflexa femoris. The catheter itself was connected to the osmotic minipump (2ML-2, Alza Corp), which was implanted under the skin of the lower abdomen. Rabbits were outfitted with a specially designed body suit that allowed them to move freely but prevented self-mutilation. They were housed together in a large cage with free access to water and chow to secure mobility. Before they were killed for study, the animals received another intramuscular injection of ketamine hydrochloride and xylazine. The animals then underwent tracheostomy and were artificially ventilated. Anesthesia was deepened with pentobarbital (12 mg/kg body wt per hour). The carotid artery was cannulated for continuous pressure monitoring. The arteria saphena magna (anterior tibial artery in humans and main arterial supply to the lower limb and foot in the rabbit) was exposed just above the ankle and cannulated with polyethylene tubing (inner diameter, 0.58 mm; outer diameter, 0.96 mm). They were connected to a Statham P23DC pressure transducer (Statham, Spectramed) for measurement of PPs. After heparinization with 5000 U heparin, both external iliac arteries were exposed and cannulated with 2.0-mm bore metal tubing. The abdominal circumflex artery and the arteria spermatica were ligated, and a tourniquet was placed proximally around both thighs, leaving the femoral artery patent. The femoral and sciatic vein were incised for drainage of venous blood. The animals then were bled, and the legs were amputated above the hip and quickly transferred to the perfusion apparatus.
Control of Successful Local Delivery of Agents
After finishing the experiment, all fluid remaining in the
reservoir of the minipump was collected and weighed. In the two control
animals receiving BrdU, BrdU staining was performed by standard
immunohistochemical methods described elsewhere.22
Ex Vivo Pressure-Flow Relations
The legs were perfused with autologous
oxygenated blood warmed to 37°C using a Stoeckert roller
pump (Stoeckert GmbH) and a Jostra M2 membrane oxygenator (Jostra
GmbH). Hematocrit was kept between 34% and 37%, and oxygen saturation
was maintained at 99%. Maximal vasodilation was achieved by adding 25
mg papaverine (Sigma) to the perfusate (priming volume, 60 mL).
The legs were perfused at three different pressure levels (40, 60, and
80 mm Hg). After stabilization, radioactive microspheres
were injected, and a reference sample was drawn using a syringe pump
(Braun Melsung). For each pressure level, microspheres labeled
either with ruthenium, cerium, and niobium or scandium (Dupont NEN
Products) were randomly chosen. This allowed us to relate tissue
perfusion to different perfusion pressures. Total flow was determined
using an ultrasonic in-line flow probe connected to a T201 flowmeter
(Transonic Systems, Inc). Systemic pressures and peripheral
capillary pressures were traced with a Statham P23DC pressure
transducer (Statham, Spectramed). All recordings were
transferred on-line to a computerized recording system (MacLab,
Apple Microsoft USA) from which they were recovered for further
processing.
Counting of Microspheres
Quadriceps, adductor longus, adductor magnus, gastrocnemius,
soleus, and peroneal muscles were dissected from the leg, and each
muscle was divided into five consecutive samples from the proximal to
the distal end. Samples were weighed and subsequently analyzed
together with the respective reference samples using a germanium
detector as described previously.23
Calculation of Flows and Conductances
For the calculation of sample flows, we used mean sample
activity (Am) per gram of muscle weight and related this to
total flow (Ft) per gram of muscle weight, which allowed
the calculation of sample flow (Fs) using the following
equation: Fs=Ft/AmxAs.
This correlated well with the calculation of Fs from sample
activity (As), reference sample activity (Ar),
weight of the reference sample (Wr), and time of reference
sample withdrawal (t), according to the following equation:
Fs=As/ArxWr/t.
Calculation of Conductances
In our model, collateral arteries developing after femoral
artery occlusion in typical corkscrew formation supply blood to the
distal adductor region and the lower leg. We measured SP and PP. Venous
pressure was equal to AP (zero, in our case). Since
arterial resistances are much lower than collateral and
peripheral resistances, they can be neglected. SP
represents the pressure at the stem region of the collateral
arteries. PP is the pressure at the reentry region and is identical to
the pressure head of the circulation in the lower leg; AP, the pressure
at the venous end of the peripheral circulation. Collateral
flow is equal to the sum of flow to the tissue of the distal adductor
plus the flow to the tissue of the lower leg. (Flow to the bone was
very small and the main arterial supply to the foot was
ligated. Therefore these values were neglected in our calculation.)
Collateral resistance was defined as pressure difference between SP and
PP divided by the flow going to the distal adductor and the lower leg.
Peripheral resistance was defined as PP divided by flow to
the lower leg, and bulk conductance was defined as SP divided by bulk
flow recorded with the ultrasonic flow probe. The reciprocal values
of these resistances represent collateral,
peripheral, and bulk conductance. Because a positive
pressure intercept is observed even at maximal vasodilation, all
conductances were calculated from the slope of pressure-flow
relations.
Postmortem Angiography
After maximal vasodilatation, legs were warmed to 37°C and
perfused with Krebs-Henseleit buffered saline for 1 minute, followed by
perfusion with contrast medium based on bismuth and gelatin according
to a formula developed by Fulton.24 Subsequently, the
contrast medium was allowed to gel by placing the limb on crushed ice
and angiograms were taken at two different angles in a Balteau
radiography apparatus (Machlett
Laboratories) using a single-enveloped Structurix D7 DW film (AGVA).
The resulting stereoscopic pictures allowed analysis of
collateral growth in three dimensions.
Perfusion Fixation and Preparation of Histological Samples
The abdominal aorta was cannulated with a 2-mm-bore metal
cannula, the chest was opened, and the heart was exposed. After
incision of the right atrium to allow drainage of rinsing solution and
fixative, perfusion was started with a rinsing solution containing
0.5% BSA, 5 mmol/L EDTA, and 0.317 mg/L adenosine in
1.5x PBS for 5 minutes, followed by fixation with 4% formalin in the
rinsing solution without BSA for 20 minutes. Subsequently, a postmortem
angiography was performed as described above. This allowed the precise
localization and excision of collateral vessels, their stems, and
reentry regions.
Analysis of Semithin Sections and Fluorescence
Microscopy
For immunohistological studies, samples were
kept in 20% saccharose overnight and then frozen and mounted on cork
in nitrogen-cooled methylbutane at -130°C. They were stored at
-80°C until further processing. For visualization of BrdU, cryostat
sections of 20 µm were obtained in a Leica CM 3000 cryotome,
mounted onto silicone-coated slides, and incubated in 2 mol/L HCl at
38°C for 20 minutes. After rinsing in PBS three times for 5 minutes,
they were incubated with the primary antibody against BrdU (clone
BU20a, DAKO Corp) at 1:20 in PBS at 4°C overnight. For detection, the
samples were incubated with a biotinylated donkey anti-mouse antibody
(DIANOVA Corp) at 1:100 in PBS for 1 hour, followed by incubation
with streptavidin-cy2 (Biotrend) at 1:100 in PBS for 30 minutes.
Finally, sections were counterstained either with 7-aminoactinomycin D
(1:50 in PBS, Molecular Probes) as a nuclear stain or phalloidin-TRITC
(1:100 in PBS) as a marker for actin. Slides were mounted in Mowiol
(Hoechst) and viewed by Leica confocal laser microscope. Neighboring
sections treated identically but omitting the primary antibody served
as a negative control. Immunohistochemical staining of capillary
endothelial cells was performed by following the
protocol described above but with an antibody against CD31 (DAKO), an
endothelium-specific antigen, as primary antibody.
Staining for macrophages was performed using RAM 11 (DAKO), a
specific antibody against rabbit macrophages as primary
antibody.
Statistical Analysis
All data are presented as mean±SEM. Intergroup
comparisons were performed by unpaired Student's t test. In
the case of unequal variances, the Mann-Whitney rank-sum test was used.
Values of P
.05 were required for assumption of statistical
significance.
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Results |
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No animal was lost during or after the primary operation. We also did not observe any gangrene or gross impairment of function after femoral artery occlusion. Two animals had to be excluded from the study because of air embolism. Of the total 27 hindlimbs that were perfused, four were excluded because PPs could not be obtained, and one was excluded from the determination of collateral and capillary conductances because of sampling errors. There were no significant differences in conductances between animals receiving PBS via minipump and animals receiving no treatment (bulk conductance, 57.2±8.60 versus 69.2±10.01 mL/min per 100 mm Hg; collateral conductance, 24.5±5.69 versus 25.3±3.29 mL/min per 100 mm Hg). Therefore, these two groups were combined in the final analysis.
Monocyte Accumulation in Response to MCP-1 Infusion
After femoral artery occlusion, monocytes/macrophages were
found to accumulate in vessel walls of excised collateral arteries and
interstitially in the lower limb (Fig 1A
and 1B). They were more numerous in animals treated with
MCP-1 (Fig 1C and 1D). Furthermore, white plaques were seen
macroscopically around the infusion site in all animals receiving
MCP-1. These plaques contained large numbers of mononuclear cells,
which predominantly were identified as monocytes/macrophages by
immunohistochemical staining with Ram 11 (DAKO GmbH).
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Control of Successful Local Delivery of Agents
Evaluation of fluids remaining in the reservoir revealed that
pumping at a rate of 10 µL/h was accomplished in all experiments.
Positive immunohistochemical staining for BrdU demonstrated that local
infusion into the collateral circulation via osmotic minipump was
feasible.
Radiographic Findings
Postmortem angiograms exhibited corkscrew collaterals mainly in
the adductor longus, adductor magnus, and vastus intermedius muscles
connecting the perfusion bed of the arteria femoralis profunda to that
of the arteria saphena parva in the adductor muscles and the perfusion
bed of the arteria circumflexa femoris lateralis to that of the
arteriae genuales in the quadriceps muscle. Angiograms taken from
hindlimbs of animals with MCP-1 treatment showed a remarkable increase
in the density of these collateral vessels (Fig 2A and 2B). No collateral vessels were visible on angiograms in
the lower limb of normal and MCP-1–treated animals.
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Proliferation of Collateral Arteries in the Thigh and Capillaries
in the Lower Limb
Collateral arteries excised after 7 days of occlusion showed
proliferation of endothelial and smooth muscle cells on
BrdU staining (Fig 3A). Proliferation of capillary
endothelial cells was seen in the lower limb, leading
to an increase in the number of capillaries 7 days after occlusion
(control leg, Fig 3B; leg after 7 days of occlusion, Fig 3C).
MCP-1–treated animals showed more capillaries in the lower limb than
did untreated animals after a week of occlusion, indicating enhancement
of capillary sprouting by MCP-1 (Fig 3D).
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Bulk Conductance
After 1 week of femoral artery occlusion, bulk conductance as
calculated from pressure flow relations was significantly higher in
animals treated with MCP-1 (142.1±31.71 versus 66.2±7.76 mL/min per
100 mm Hg, P<.05) (Fig 4). After 7
days of occlusion, bulk conductances for MCP-1–treated animals reached
levels even higher than those for untreated animals after 3 weeks of
femoral artery occlusion and were comparable to values in nonoccluded
hindlimbs.
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P<.05
compared with 1 week of occlusion without MCP-1 treatment.
Collateral Conductance
Collateral conductance also was significantly higher after 1 week
of occlusion in animals treated with MCP-1 compared with animals
without this treatment (70.6±19.23 versus 25.1±2.59 mL/min per
100 mm Hg, P<.01) (Fig 5). Collateral
conductance of animals that had received MCP-1 for 1 week tended to be
even larger than that in untreated animals after 3 weeks of femoral
artery occlusion.
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Peripheral Conductance in the Calf
Conductance in the calf also was significantly higher after 1 week
of femoral artery occlusion in animals with MCP-1 treatment compared
with rabbits that had not received MCP-1 (119.3±22.37 versus
45.4±6.80 mL/min per 100 mm Hg, P<.05) (Fig 6).
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P<.05
compared with control animals. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study demonstrates that local infusion of MCP-1 increases both collateral and peripheral conductance after femoral artery occlusion. Angiographic and histological findings suggest that this increase in conductance is due to enhanced vessel growth either by augmentation of monocyte accumulation or by unknown direct proliferative effects of MCP-1 on endothelial and/or smooth muscle cells. MCP-1 is a 14-kD glycoprotein secreted by many cells, including vascular smooth muscle and endothelial cells25 26 27 28 and induces monocyte chemotaxis at subnanomolar concentrations.29 MCP-1 is a potent agonist for the ß-chemokine receptors CCR 2 and CCR 4, which are both mainly expressed by monocytes but also have been found to be present on basophils and T and B lymphocytes.30 These G protein–coupled seven-transmembrane-domain receptors lead to the activation of monocytes and increased adhesiveness of integrins, a process that finally leads to monocyte arrest on endothelial cells.31 The MCP-1 gene can be induced by various cytokines (ie, tumor necrosis factor-
)
and IgG.32 Recently, it has been shown in vitro that gene
expression and protein secretion of MCP-1 are also upregulated by shear
stress and cyclic strain.16 17 18 Moreover, increased levels
of MCP-1 mRNA were found in ischemic tissue of
microembolized porcine myocardium21 as
well as in reperfused ischemic
myocardium.33 The MCP-1 gene is well preserved
and shows large interspecies homologies.26 In the
present study, the human form of the MCP-1 protein was administered
locally via osmotic minipump. Positive immunohistochemical staining for
BrdU infused into two animals via the same route as MCP-1 demonstrated
that local delivery of substances into the collateral circulation was
feasible. By macroscopic inspection of the injection site and
histological examination of collateral arteries from
the thigh and tissue sections from calf muscles, it became evident that
MCP-1 injection had led to an increase of monocyte accumulation in our
experiment. Positive staining of excised collateral arteries for BrdU
provided evidence that collateral vessels observed by angiography of
the thigh were truly proliferating. For quantification of
hemodynamic changes, we chose an ex vivo model for
better control of perfusion pressures and flows. In this model,
pressure-flow relations were obtained under maximal vasodilation in a
controlled and defined anatomic and physiological
environment, a situation that is impossible to accomplish in vivo
because of the deleterious effect of maximal vasodilation on blood
pressure and the diversion of a large fraction of flow from the leg to
the trunk region as described before (up to 28% according to Gorski et
al34 ). Maximal vasodilation by papaverine during all
hemodynamic measurements ensured that the effects seen
were definitely not due to vasodilatory effects of MCP-1. Furthermore,
immunohistochemical studies after continuous BrdU infusion clearly
demonstrated that collateral vessel formation in the thigh involved
proliferation of endothelial and smooth muscle cells,
given the fact that the normal generation time for
endothelial cells and for smooth muscle cells is at
least 6 months and that proliferation is usually not seen in normal
arteries.35 The degree of proliferation is similar to that
of collateral arteries in the dog heart after ameroid constrictor
placement and approaches that of tumors.36 Although this
does not exclude the possibility that MCP-1 enhances collateral artery
proliferation via hypothetical unrecognized chronic vasodilatory
effects, the rapidity and magnitude of the increase in collateral
conductance is far higher than with any other known
vasodilator.37 38 39 40 Furthermore, monocytes have been shown
to downregulate nitric oxide synthase, a very potent vasodilator, in
cultured aortic endothelial cells, suggesting that
MCP-1 would rather inhibit than enhance vasodilation.41
Therefore, vasodilation is a very unlikely explanation for our
findings. The higher density of collateral arteries on our angiograms
further supports the notion that collateral artery growth is
responsible for the increase in collateral conductance. In contrast to the thigh, where the density of collateral arteries increased, more capillaries were found in histological sections from calf muscles of MCP-1–treated animals compared with control animals after 7 days of occlusion. We chose an antibody against CD31 (PECAM) as a marker for endothelial cells because this cell adhesion molecule is constitutively expressed on all endothelial cells and not dependent on their phenotype or activation.42 43 Using BrdU as a marker for proliferation, we were able to detect only proliferating capillaries in the calf muscles. No other vessel type was found to grow in this region. As for collateral conductance, we excluded passive vessel enlargement due to vasodilation as a reason for peripheral conductance changes by performing our measurements at maximal vasodilatation. Thus, changes in peripheral conductance are most likely attributable to capillary sprouting.
Both collateral and peripheral conductance were increased 2-fold in animals treated with MCP-1 compared with untreated animals after 7 days of femoral artery occlusion. Thus, animals locally injected with MCP-1 reached normal conductance values after 1 week of occlusion, whereas conductance values in untreated animals did not return to normal levels even 3 weeks after occlusion. As mentioned above, MCP-1 is mainly known as a chemoattractant for monocytes.27 31 One possible explanation would therefore be that MCP-1 exerts its pronounced effects on collateral and peripheral conductance via attraction and activation of monocytes that, in turn, produce growth factors that lead to the proliferation of endothelial and smooth muscle cells. This requires that monocytes adhere to the small arteriolar connections, which are very likely the origin of our collateral arteries.31 44 45 These preexisting arteriolar connections experience a large increase in shear stress when the main arterial supply to the lower leg is occluded. However, it is difficult to predict what happens in these vessels from the findings of previous studies: Initial rolling of monocytes is mediated by P- and L-selectin, followed by the activation of chemokine receptors, which leads to the increased adhesiveness of integrins.31 46 The arrest of monocytes on endothelial cells can either be mediated by the integrin counterreceptors ICAM or VECAM.31 44 45 46 ICAM, which contains SSRE in the promoter of its gene, has been shown to be upregulated by shear stress in numerous studies.47 48 In contrast, VECAM, which does not possess SSRE, has been shown to be downregulated by shear stress.49 50 51 52 In the carotid artery, monocytes adhere under low rather than high shear stress, but the high shear stress in the study is much lower than that expected in collateral arteries.53 The interpretation of these data is further complicated by the fact that the expression of cell adhesion molecules very much depends on the type of vessel studied.31 To date, however, no study exists showing the expression of cell adhesion molecules in collateral arteries in vivo. In contrast, they have been shown to play an important role in monocyte migration during atherogenesis.54 55 Collateral growth and atherogenesis share many features, such as smooth muscle proliferation and neointima formation. Whereas these proliferating processes may lead to the occlusion of vessels in atherogenesis, they contribute to the enlargement of vessels in collateral artery growth. This requires pronounced remodeling processes to create sufficient space for the newly developing vessel. Since monocytes have been shown to play an important role in apoptosis, they may not only contribute to proliferation but also to remodeling processes during collateral growth.56 57 Our histological data suggest that more monocytes accumulate in MCP-1–treated animals. Since monocytes are potentially capable of producing large amounts of growth factors, this further supports the hypothesis that monocytes are the mediator of the changes seen with MCP-1 treatment. The change in monocyte accumulation in MCP-1–treated animals, however, is not as pronounced as one may expect. Therefore, we cannot exclude the possibility that MCP-1 exerts its pronounced effects on collateral conductance via direct mechanisms, although they have not yet been described. Chemokine receptors are G protein–coupled and therefore may be envisaged to mediate actions other than monocyte activation and attraction.31 Thus far, only the chemokine receptor CCR 3, which is not a receptor for MCP-1, has been suggested to be present on endothelial cells.58 59 60
In the present study, we observed an increase not only in collateral but also in peripheral conductance with MCP-1 infusion. In previous studies using the pig ameroid constrictor or microembolization model, we observed capillary sprouting mainly around microinfarcts.1 As mentioned above, angiogenesis in these models was also associated with the accumulation and migration of monocytes.1 20 These results suggest that inflammation in addition to hypoxia is a major component of angiogenesis.
In summary, our results have shown that local infusion of MCP-1, a potent and specific chemoattractant for monocytes, is able to markedly increase collateral as well as peripheral conductance. Angiographic and histological findings indicate that this effect is due to augmented collateral artery and capillary proliferation. Together with our previous findings in the dog and pig heart, these results suggest that adhesion, activation, and migration of monocytes may play an important role in both types of vessel growth.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Ito was supported by a postdoctoral research scholarship from the German Cardiac Society.
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Footnotes |
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1 Both authors contributed equally to this study.
Received September 26, 1996; accepted February 21, 1997.
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 R.P. Dai, S.T. Dheen, B.P. He, and S.S.W. Tay Differential expression of cytokines in the rat heart in response to sustained volume overload Eur J Heart Fail, October 1, 2004; 6(6): 693 - 703. [Abstract] [Full Text] [PDF]
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E. Khmelewski, A. Becker, T. Meinertz, and W. D. Ito Tissue Resident Cells Play a Dominant Role in Arteriogenesis and Concomitant Macrophage Accumulation Circ. Res., September 17, 2004; 95(6): e56 - e64. [Abstract] [Full Text] [PDF]
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M. Heil and W. Schaper Influence of Mechanical, Cellular, and Molecular Factors on Collateral Artery Growth (Arteriogenesis) Circ. Res., September 3, 2004; 95(5): 449 - 458. [Abstract] [Full Text] [PDF]
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 B. M. Prior, H. T. Yang, and R. L. Terjung What makes vessels grow with exercise training? J Appl Physiol, September 1, 2004; 97(3): 1119 - 1128. [Abstract] [Full Text] [PDF]
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 E. Schneeloch, G. Mies, H.-J. Busch, I. R. Buschmann, and K.-A. Hossmann Granulocyte-macrophage colony-stimulating factor-induced arteriogenesis reduces energy failure in hemodynamic stroke PNAS, August 24, 2004; 101(34): 12730 - 12735. [Abstract] [Full Text] [PDF]
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T. Kinnaird, E. Stabile, M. S. Burnett, and S. E. Epstein Bone Marrow-Derived Cells for Enhancing Collateral Development: Mechanisms, Animal Data, and Initial Clinical Experiences Circ. Res., August 20, 2004; 95(4): 354 - 363. [Abstract] [Full Text] [PDF]
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H. Niiyama, H. Kai, T. Yamamoto, T. Shimada, K.-I. Sasaki, T. Murohara, K. Egashira, and T. Imaizumi Roles of endogenous monocyte chemoattractant protein-1 in ischemia-induced neovascularization J. Am. Coll. Cardiol., August 4, 2004; 44(3): 661 - 666. [Abstract] [Full Text] [PDF]
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T. Kurotobi, H. Sato, K. Kinjo, D. Nakatani, H. Mizuno, M. Shimizu, K. Imai, A. Hirayama, K. Kodama, M. Hori, et al. Reduced collateral circulation to the infarct-related artery in elderly patients with acute myocardial infarction J. Am. Coll. Cardiol., July 7, 2004; 44(1): 28 - 34. [Abstract] [Full Text] [PDF]
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I. E. Hoefer, N. van Royen, J. E. Rectenwald, E. Deindl, J. Hua, M. Jost, S. Grundmann, M. Voskuil, C. K. Ozaki, J. J. Piek, et al. Arteriogenesis Proceeds via ICAM-1/Mac-1- Mediated Mechanisms Circ. Res., May 14, 2004; 94(9): 1179 - 1185. [Abstract] [Full Text] [PDF]
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A. Parenti, L. Bellik, L. Brogelli, S. Filippi, and F. Ledda Endogenous VEGF-A is responsible for mitogenic effects of MCP-1 on vascular smooth muscle cells Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1978 - H1984. [Abstract] [Full Text] [PDF]
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G. Pasterkamp, Z. S. Galis, and D. P.V. de Kleijn Expansive Arterial Remodeling: Location, Location, Location Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 650 - 657. [Abstract] [Full Text] [PDF]
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M. Heil, T. Ziegelhoeffer, S. Wagner, B. Fernandez, A. Helisch, S. Martin, S. Tribulova, W. A. Kuziel, G. Bachmann, and W. Schaper Collateral Artery Growth (Arteriogenesis) After Experimental Arterial Occlusion Is Impaired in Mice Lacking CC-Chemokine Receptor-2 Circ. Res., March 19, 2004; 94(5): 671 - 677. [Abstract] [Full Text] [PDF]
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T. Ziegelhoeffer, B. Fernandez, S. Kostin, M. Heil, R. Voswinckel, A. Helisch, and W. Schaper Bone Marrow-Derived Cells Do Not Incorporate Into the Adult Growing Vasculature Circ. Res., February 6, 2004; 94(2): 230 - 238. [Abstract] [Full Text] [PDF]
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S. C.G. Hollestelle, M. R. de Vries, J. K. van Keulen, A. H. Schoneveld, A. Vink, C. F. Strijder, B. J. van Middelaar, G. Pasterkamp, P. H.A. Quax, and D. P.V. de Kleijn Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling Circulation, January 27, 2004; 109(3): 393 - 398. [Abstract] [Full Text] [PDF]
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M. Strasly, G. Doronzo, P. Capello, D. Valdembri, M. Arese, S. Mitola, P. Moore, G. Alessandri, M. Giovarelli, and F. Bussolino CCL16 activates an angiogenic program in vascular endothelial cells Blood, January 1, 2004; 103(1): 40 - 49. [Abstract] [Full Text] [PDF]
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K. Kondoh, H. Koyama, T. Miyata, T. Takato, H. Hamada, and H. Shigematsu Conduction performance of collateral vessels induced by vascular endothelial growth factor or basic fibroblast growth factor Cardiovasc Res, January 1, 2004; 61(1): 132 - 142. [Abstract] [Full Text] [PDF]
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S. Fujiyama, K. Amano, K. Uehira, M. Yoshida, Y. Nishiwaki, Y. Nozawa, D. Jin, S. Takai, M. Miyazaki, K. Egashira, et al. Bone Marrow Monocyte Lineage Cells Adhere on Injured Endothelium in a Monocyte Chemoattractant Protein-1-Dependent Manner and Accelerate Reendothelialization as Endothelial Progenitor Cells Circ. Res., November 14, 2003; 93(10): 980 - 989. [Abstract] [Full Text] [PDF]
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N. C. Weber, S. B. Blumenthal, T. Hartung, A. M. Vollmar, and A. K. Kiemer ANP inhibits TNF-{alpha}-induced endothelial MCP-1 expression--involvement of p38 MAPK and MKP-1 J. Leukoc. Biol., November 1, 2003; 74(5): 932 - 941. [Abstract] [Full Text] [PDF]
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 V. Chhokar and A. L. Tucker Angiogenesis: Basic Mechanisms and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 253 - 280. [Abstract] [PDF]
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K. Boengler, F. Pipp, B. Fernandez, T. Ziegelhoeffer, W. Schaper, and E. Deindl Arteriogenesis is associated with an induction of the cardiac ankyrin repeat protein (carp) Cardiovasc Res, September 1, 2003; 59(3): 573 - 581. [Abstract] [Full Text] [PDF]
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I. R. Buschmann, H.-J. Busch, G. Mies, and K.-A. Hossmann Therapeutic Induction of Arteriogenesis in Hypoperfused Rat Brain Via Granulocyte-Macrophage Colony-Stimulating Factor Circulation, August 5, 2003; 108(5): 610 - 615. [Abstract] [Full Text] [PDF]
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W. Schaper and D. Scholz Factors Regulating Arteriogenesis Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1143 - 1151. [Abstract] [Full Text] [PDF]
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M. Voskuil, N. van Royen, I. E. Hoefer, R. Seidler, B. D. Guth, C. Bode, W. Schaper, J. J. Piek, and I. R. Buschmann Modulation of collateral artery growth in a porcine hindlimb ligation model using MCP-1 Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1422 - H1428. [Abstract] [Full Text] [PDF]
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E. Deindl, I. E. Hoefer, B. Fernandez, M. Barancik, M. Heil, M. Strniskova, and W. Schaper Involvement of the Fibroblast Growth Factor System in Adaptive and Chemokine-Induced Arteriogenesis Circ. Res., March 21, 2003; 92(5): 561 - 568. [Abstract] [Full Text] [PDF]
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F. Pipp, M. Heil, K. Issbrucker, T. Ziegelhoeffer, S. Martin, J. van den Heuvel, H. Weich, B. Fernandez, G. Golomb, P. Carmeliet, et al. VEGFR-1-Selective VEGF Homologue PlGF Is Arteriogenic: Evidence for a Monocyte-Mediated Mechanism Circ. Res., March 7, 2003; 92(4): 378 - 385. [Abstract] [Full Text] [PDF]
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J. B. Buckwalter, V. C. Curtis, Z. Valic, S. B. Ruble, and P. S. Clifford Endogenous vascular remodeling in ischemic skeletal muscle: a role for nitric oxide J Appl Physiol, March 1, 2003; 94(3): 935 - 940. [Abstract] [Full Text] [PDF]
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N. van Royen, I. Hoefer, M. Bottinger, J. Hua, S. Grundmann, M. Voskuil, C. Bode, W. Schaper, I. Buschmann, and J.J. Piek Local Monocyte Chemoattractant Protein-1 Therapy Increases Collateral Artery Formation in Apolipoprotein E-Deficient Mice but Induces Systemic Monocytic CD11b Expression, Neointimal Formation, and Plaque Progression Circ. Res., February 7, 2003; 92(2): 218 - 225. [Abstract] [Full Text] [PDF]
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N van Royen, I Hoefer, I Buschmann, S Kostin, M Voskuil, C. Bode, W Schaper, and J.J Piek Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits Cardiovasc Res, January 1, 2003; 57(1): 178 - 185. [Abstract] [Full Text] [PDF]
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M. Heil, T. Ziegelhoeffer, F. Pipp, S. Kostin, S. Martin, M. Clauss, and W. Schaper Blood monocyte concentration is critical for enhancement of collateral artery growth Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2411 - H2419. [Abstract] [Full Text] [PDF]
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J. Song, M. Qi, S. Kaul, and R. J. Price Stimulation of Arteriogenesis in Skeletal Muscle by Microbubble Destruction With Ultrasound Circulation, September 17, 2002; 106(12): 1550 - 1555. [Abstract] [Full Text] [PDF]
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R. J. Price and S. Kaul Contrast Ultrasound Targeted Drug and Gene Delivery: An Update on a New Therapeutic Modality Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2002; 7(3): 171 - 180. [Abstract] [PDF]
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A. Parenti, L. Brogelli, S. Filippi, S. Donnini, and F. Ledda Effect of hypoxia and endothelial loss on vascular smooth muscle cell responsiveness to VEGF-A: role of flt-1/VEGF-receptor-1 Cardiovasc Res, July 1, 2002; 55(1): 201 - 212. [Abstract] [Full Text] [PDF]
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 D. H. Townson, C. L. O'Connor, and J. K. Pru Expression of Monocyte Chemoattractant Protein-1 and Distribution of Immune Cell Populations in the Bovine Corpus Luteum Throughout the Estrous Cycle Biol Reprod, February 1, 2002; 66(2): 361 - 366. [Abstract] [Full Text] [PDF]
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T. O. Nossuli, N. G. Frangogiannis, P. Knuefermann, V. Lakshminarayanan, O. Dewald, A. J. Evans, J. Peschon, D. L. Mann, L. H. Michael, and M. L. Entman Brief murine myocardial I/R induces chemokines in a TNF-alpha -independent manner: role of oxygen radicals Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2549 - H2558. [Abstract] [Full Text] [PDF]
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V. Lindner and T. Maciag The Putative Convergent and Divergent Natures of Angiogenesis and Arteriogenesis Circ. Res., October 26, 2001; 89(9): 747 - 749. [Full Text] [PDF]
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C. Seiler, T. Pohl, K. Wustmann, D. Hutter, P.-A. Nicolet, S. Windecker, F. R. Eberli, and B. Meier Promotion of Collateral Growth by Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Coronary Artery Disease: A Randomized, Double-Blind, Placebo-Controlled Study Circulation, October 23, 2001; 104(17): 2012 - 2017. [Abstract] [Full Text] [PDF]
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V. Lakshminarayanan, M. Lewallen, N. G. Frangogiannis, A. J. Evans, K. E. Wedin, L. H. Michael, and M. L. Entman Reactive Oxygen Intermediates Induce Monocyte Chemotactic Protein-1 in Vascular Endothelium after Brief Ischemia Am. J. Pathol., October 1, 2001; 159(4): 1301 - 1311. [Abstract] [Full Text]
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S. E. Epstein, R. Kornowski, S. Fuchs, and H. F. Dvorak Angiogenesis Therapy : Amidst the Hype, the Neglected Potential for Serious Side Effects Circulation, July 3, 2001; 104(1): 115 - 119. [Full Text] [PDF]
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S. Fuchs, R. Baffour, Y. F. Zhou, M. Shou, A. Pierre, F. O. Tio, N. J. Weissman, M. B. Leon, S. E. Epstein, and R. Kornowski Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1726 - 1732. [Abstract] [Full Text] [PDF]
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M. J. Post, R. Laham, F. W. Sellke, and M. Simons Therapeutic angiogenesis in cardiology using protein formulations Cardiovasc Res, February 16, 2001; 49(3): 522 - 531. [Abstract] [Full Text] [PDF]
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S. E. Epstein, S. Fuchs, Y. F. Zhou, R. Baffour, and R. Kornowski Therapeutic interventions for enhancing collateral development by administration of growth factors: basic principles, early results and potential hazards Cardiovasc Res, February 16, 2001; 49(3): 532 - 542. [Abstract] [Full Text] [PDF]
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N. van Royen, J. J. Piek, I. Buschmann, I. Hoefer, M. Voskuil, and W. Schaper Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease Cardiovasc Res, February 16, 2001; 49(3): 543 - 553. [Abstract] [Full Text] [PDF]
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J. Waltenberger Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications Cardiovasc Res, February 16, 2001; 49(3): 554 - 560. [Abstract] [Full Text] [PDF]
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I. E. Hoefer, N. van Royen, I. R. Buschmann, J. J. Piek, and W. Schaper Time course of arteriogenesis following femoral artery occlusion in the rabbit Cardiovasc Res, February 16, 2001; 49(3): 609 - 617. [Abstract] [Full Text] [PDF]
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J. C. Hershey, E. P. Baskin, J. D. Glass, H. A. Hartman, D. B. Gilberto, I. T. Rogers, and J. J. Cook Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis Cardiovasc Res, February 16, 2001; 49(3): 618 - 625. [Abstract] [Full Text] [PDF]
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